Cannabidiol may ease Alzheimer’s-related brain inflammation and improve cognition

A new study published in the journal eNeuro provides evidence that cannabidiol (CBD), a nonpsychoactive compound derived from cannabis, may help reduce brain inflammation associated with Alzheimer’s disease. In a series of experiments using a well-established mouse model of the disease, researchers at Augusta University found that daily inhalation of CBD reduced inflammatory markers in the brain and led to improvements in memory-related behaviors. These findings support the idea that CBD could serve as a potential treatment that targets the immune system’s role in Alzheimer’s.

Alzheimer’s disease is the most common form of dementia, affecting millions of people worldwide. It causes progressive memory loss, confusion, and eventually a decline in physical function. For decades, researchers have focused on two hallmark features of the disease: amyloid plaques and tau tangles, both of which accumulate in the brain. But many scientists now believe these markers do not fully explain how or why the disease develops.

Emerging theories suggest that chronic immune system dysfunction, particularly in the brain, plays a major role in the progression of Alzheimer’s. In this view, inflammation does not just happen as a consequence of brain damage; it may be a central force driving the disease. Two key pathways in this process are the indoleamine 2,3-dioxygenase (IDO) enzyme and the cyclic GMP-AMP synthase (cGAS) signaling pathway. These systems are known to regulate immune responses in the brain and have been implicated in other inflammatory and degenerative conditions.

CBD has attracted attention for its anti-inflammatory properties, and earlier studies have shown that it can reduce some features of Alzheimer’s in animal models. What remained unclear was whether CBD could directly influence the immune pathways thought to be active in the disease. The researchers aimed to investigate whether CBD could regulate IDO and cGAS activity and whether doing so might lead to reduced brain inflammation and improved cognitive function.

“Alzheimer’s disease remains one of the most pressing challenges in medicine, affecting millions of families worldwide, yet there is still no truly effective treatment. For decades, research has centered on amyloid plaques and tau tangles, but the continued lack of success in clinical trials suggests that Alzheimer’s is more complex than just protein buildup,” said study author Babak Baban, a professor and associate dean for research at the Medical College of Georgia at Augusta University.

“Our team wanted to explore a different angle, one rooted in immune dysregulation and chronic inflammation. We approached Alzheimer’s as an autoinflammatory disease, where the brain’s immune system becomes overactive and self-perpetuating. CBD, known for its powerful anti-inflammatory and immunomodulatory properties, offered a novel tool to test this hypothesis.”

The study used male mice genetically engineered to develop Alzheimer’s-like symptoms. These mice, known as 5xFAD mice, carry human gene mutations that lead to early and aggressive buildup of amyloid plaques in the brain. Starting at nine to twelve months of age, the mice received either a placebo or daily doses of CBD delivered through a modified inhaler for four weeks. This method of administration was chosen because it allows faster absorption into the body compared to oral delivery, providing a more consistent exposure.

To examine the effects of CBD, the researchers collected brain tissue and conducted a series of imaging and immune cell analyses. They focused specifically on the entorhinal cortex, a brain region involved in memory that is often affected early in Alzheimer’s. They also conducted behavioral tests to assess changes in memory and anxiety-like behaviors.

The team used fluorescent staining to track the presence of IDO and cGAS in brain cells, especially microglia and astrocytes. These are the brain’s resident immune cells and are known to become activated in Alzheimer’s. They also used flow cytometry to measure changes in immune cell populations and the levels of signaling molecules known as cytokines, which promote or suppress inflammation. To explore how these findings might relate to behavior, the researchers used open field and novel object recognition tests. These are commonly used to evaluate memory and exploration in animal studies.

After four weeks of treatment, the researchers observed a significant reduction in IDO expression in both microglia and astrocytes of CBD-treated mice compared to controls. This suggests that CBD was able to alter immune cell activity in the brain. Although not statistically significant, there were signs of increased microglial activation and decreased astrocytic activity, patterns that are often considered favorable in the context of Alzheimer’s.

The researchers also found a decrease in cGAS expression in the same brain regions, particularly in cells that were already expressing IDO. This co-occurrence indicates that CBD may influence a shared immune-metabolic pathway involved in chronic inflammation.

“The degree of interaction between the two immune pathways was greater than expected,” Baban told PsyPost. “Both IDO and cGAS were already known to contribute to inflammation independently, but our results show they operate in close coordination. Even more surprising was how effectively CBD could regulate both at once, revealing a unified mechanism of immune control in the brain.”

Flow cytometry analysis revealed that CBD-treated mice had fewer infiltrating macrophages in the brain. These are immune cells that travel from the bloodstream and are often associated with heightened inflammatory responses. CBD also lowered levels of inflammatory cytokines such as interferon-gamma, interleukin-1 beta, and tumor necrosis factor-alpha. At the same time, it increased levels of interleukin-10, an anti-inflammatory molecule. These changes point to a shift from a proinflammatory to a more balanced immune environment.

Behavioral testing provided further support for CBD’s effects. In the open field test, CBD-treated mice spent more time exploring the central area of the arena, which suggests reduced anxiety. In the novel object recognition test, these mice showed a stronger preference for exploring new objects, a sign of improved memory. These behavioral improvements occurred alongside the changes seen in immune markers.

To better understand how CBD might interact with immune-related proteins, the researchers also conducted a bioinformatics analysis. Using a protein interaction database, they identified several targets that CBD may influence. Among them were AKT1, TRPV1, and GPR55, proteins involved in regulating immune responses, metabolism, and cell signaling. These molecules are connected to the IDO and cGAS pathways and may help explain how CBD modulates brain inflammation.

“Although this work is preclinical, the magnitude of both molecular and behavioral improvements was striking,” Baban said. “CBD treatment not only reduced brain inflammation but also improved memory and cognitive performance in our animal models. These findings support the idea that targeting immune pathways could complement or even surpass traditional amyloid-focused therapies.”

The findings suggest that CBD affects more than just symptoms. It appears to influence some of the underlying immune mechanisms associated with Alzheimer’s disease. By modulating pathways like IDO and cGAS, CBD may help restore immune balance in the brain. This fits with a growing perspective in the scientific community that Alzheimer’s may be driven in part by chronic, self-sustaining inflammation.

“The idea that Alzheimer’s might be an autoinflammatory disease is quite new, it began gaining traction only in 2022,” Baban told PsyPost. “Our study is the first to connect two major immune pathways, IDO and cGAS–STING, as key drivers of this inflammation. And importantly, we also show for the first time that inhaled CBD can calm both pathways simultaneously. That dual discovery, linking IDO and cGAS in Alzheimer’s and identifying CBD as a potential therapy, marks a new direction for treating the disease beyond amyloid and tau.”

Still, the study has some limitations. It was conducted in mice, and results from animal models do not always translate directly to humans. Only one dose and duration of CBD was tested, so it remains unclear what the optimal treatment strategy might be. The study also focused on a specific type of immune cell and did not examine all the possible interactions at play. Finally, while the researchers measured the presence of cGAS, they did not assess all the downstream signals it might trigger.

One point the researchers also emphasize is that CBD should not be seen as a cure. Instead, it may offer a way to adjust the immune system’s behavior and potentially slow the course of the disease.

“CBD is not a ‘cure’ for Alzheimer’s, and our findings should not be interpreted that way,” Baban said. “What we’ve demonstrated is a mechanistic foundation, that CBD functions as a precision immune modulator. It doesn’t shut down the immune system; it restores balance. This distinction matters because it shows how CBD could help recalibrate immune activity in a safe and physiologically intelligent way.”

The team is already working to move this line of research toward clinical trials and has submitted an application to the U.S. Food and Drug Administration to begin testing inhaled CBD in people with Alzheimer’s and other brain disorders. They also plan to explore whether similar immune pathways are active in related diseases like vascular dementia and autoimmune conditions.

“Our next goal is to translate these discoveries into clinical application,” Baban explained. “We currently have an Investigational New Drug (IND) application pending with the U.S. Food and Drug Administration (FDA) to advance inhaled CBD as a therapeutic for brain disorders, including Alzheimer’s and glioblastoma.”

“We are also extending this research into vascular dementia and autoimmune models, as these conditions share similar inflammatory pathways. Ultimately, we hope to redefine neurodegeneration as a disease of immune imbalance, and to build therapies that restore the brain’s homeostasis, not just remove its symptoms.”

The study, “Rethinking Alzheimer’s: Harnessing Cannabidiol to Modulate IDO and cGAS Pathways for Neuroinflammation Control,” was authored by Sahar Emami Naeini, Bidhan Bhandari, Breanna Hill, Nayeli Perez-Morales, Hannah M. Rogers, Hesam Khodadadi, Nancy Young, Lívia Maria Maciel, Jack C. Yu, David C. Hess, John C. Morgan, Évila Lopes Salles, Lei P. Wang and Babak Baban.